Aging of reward dopamine tracts in the human brain: A diffusion tensor imaging study

The mesocortical tract (MCT) and mesolimbic tract (MLT) are reward dopaminergic tracts that have been shown to play a role in regulating reward stimuli, including both incentive salience and social stimuli. In the current study, we examined aging of the MCT and MLT in normal human participants to explain human brain structures using diffusion tensor tractography (DTT). Sixty-four healthy participants were recruited for this study and allocated to 3 groups based on participants’ age. Diffusion tensor imaging was performed, and MCTs and MLTs were reconstructed using the probabilistic tractography method. A significant negative correlation was observed between age and fractional anisotropy and tract volume of the MCT and MLT, whereas a positive correlation was observed between age and mean diffusivity. The mean fractional anisotropy value of the MCT was significantly lower in the old group than in the young and middle-aged groups (P < .05). The mean diffusivity values of the MCT and MLT were significantly higher in the old group than in the young and middle-aged groups (P < .05). The mean tract volume values of the MCT and MLT were significantly lower in the old group than in the young group (P < .05). We found that degenerative changes in the MCT and MLT began in participants in the 20s–30s, progressed steadily throughout life, and accelerated in the 60s.


Introduction
The mesocortical tract (MCT) and mesolimbic tract (MLT) are the major dopamine tracts involved in reward in the human brain. [1]he MCT originates from the ventral tegmental area (VTA) and extends to the prefrontal cortex (PFC), including the orbitofrontal cortex, anterior cingulate cortex, and striatum.The MLT originates from the VTA and extends to the nucleus accumbens. [1]hese tracts are specifically important for rewards associated with cognitive control, motivation, and emotional responses. [2]revious research has highlighted the severe consequences of impairments in these tracts.For instance, anomalies in the MCT have been linked with increased white matter hyperintensities in drug addicts, affecting their decision-making and response inhibition capacities. [3][6][7][8] The MLT, when compromised, leads to behavioral control issues, fostering cravings, withdrawal symptoms, and tolerance.Such impairments can result in nondrug addictions like gambling, shopping, and video game addictions. [9]Additionally, it has been observed that MLT impairments can influence social interactions, leading to deficits in normal children compared to those with autism. [10]nderstanding the typical aging patterns of these specific brain structures is paramount.13][14] Recently, many diffusion tensor tractography (DTT) studies have been performed because this modern technique enables three-dimensional qualitative visualization and analysis of neural structures.[17][18][19][20][21][22][23] To the best of our knowledge, no study has addressed the effects of aging on these tracts.
In the current study, we investigated age-related changes in the MCT and MLT among dopaminergic pathways using DTT to compare differences in aging as a neuroimaging technique in this study.included hose in their 60s and 70s. [24]All participants provided written informed consent prior to study commencement, and the study protocol was approved by the institutional review board of the University Hospital.

DTI acquisition
Diffusion tensor imaging (DTI) data were acquired using a Synergy-L SENSE head coil on a 1.5T Gyroscan Intera system (Philips, Best, The Netherlands) equipped with single-shot echo-planar imaging.For each of the 32 non-collinear diffusion-sensitizing gradients, 67 contiguous slices were acquired parallel to the anterior commissure-posterior commissure line.

Fiber tracking
The Oxford Centre for functional magnetic resonance imaging of the brain software library (FSL; www.fmrib.ox.ac.uk/fsl) was used to analyze the diffusion-weighted imaging data. [25,26]fine multi-scale two-dimensional registration was used to correct for head motion effects and image distortions caused by eddy currents.28][29] The MCT and MLT were delineated by selecting fibers that passed through the seed and target regions of interest (ROIs).For each participant, as in the MCT, the seed ROI was placed on the VTA in the midbrain, and the target ROI was located in the PFC at the inferior frontal sulcus (Fig. 1). [30]For the MLT, the seed ROI was placed on the VTA in the midbrain, and the target ROI was located in the nucleus accumbens of the VS (Fig. 1). [30]Fractional anisotropy (FA), mean diffusivity (MD), and tract volume (TV) of the MCT and MLT were measured.

Statistical analysis
Data were analyzed using SPSS software (version 25.0; SPSS Inc., Chicago, IL).Pearson correlation analysis was performed to assess the significance of the correlations between  One-way ANOVA with Bonferroni post hoc test was used to determine the significance of differences for each DTI parameter (FA, MD, and TV) between the 3 groups.Statistical significance was set at P < .05.

Results
The correlations between age and the DTI parameters of the MCT are shown in Figure 2. We observed a significant moderate positive correlation between age and MD of the MCT (R = 0.556, P < .05)and a significantly weak negative correlation between age and FA and TV values of the MCT (r = −0.337,r = −0.368,P < .05)(Fig. 2).In addition, there were significant differences in the mean FA, MD, and TV values of the MCT among the 3 groups (P < .05)(Fig. 2) (Table 1).
The mean FA values of the MCT were higher in the young and middle-aged groups than in the old group (P < .05).The mean MD values of the MCT were lower in the young and middle-aged groups than in the old group (P < .05).TV values of the MCT were higher in the young group than in the old group (P < .05).
In terms of the MLT, a significant moderate positive correlation was observed between age and MD of the MLT (R = 0.432, P < .05)and a significant weak and moderate negative correlation between age and FA and TV values of the MLT (r = −0.201,r = −0.489,P < .05)(Fig. 3).Among the 3 groups, there were significant differences in both MD and TV values of the MLT (P < .05)(Fig. 3) (Table 2).The mean MD values of the MLT were lower in the young and middle-aged groups than in the old   TV values of the MLT were higher in the young group than in the other groups (P < .05).However, the mean FA values of the MLT were not significantly different among the 3 groups (P > .05).

Discussion
We used DTI to compare differences in aging as a neuroimaging technique by investigating age-related changes in the MCT and MLT among dopaminergic pathways.We obtained values of 3 DTI parameters: FA, MD, and TV.FA values refer to the degree of directionality and integrity of white matter microstructures, such as axons, myelin, and microtubules. [31,32]In contrast, the MD values reflect the magnitude of water diffusion. [31,32]TV values indicate the total number of fibers in a neural pathway. [31,33]n other words, reducing the FA and TV values and increasing the MD values could be considered "degeneration." [34,35]e found an overall decreasing tendency in the FA and TV and increasing tendency in the MD of the MCT and MLT with aging.In terms of the MCT, FA values of the old group were significantly lower than those of the young and middle-aged groups.According to TV values, the old group had significantly lower TV values than the young group.Moreover, MD values of the old group were significantly greater than those of the young and middle-aged groups.This suggests that the decline in TV of the MCT begins around the age of 20 years.Reduction in FA and increase in MD of the MCT indicated that demyelination of the MCT accelerated around the age of 60 years.In case of the MLT, FA values were not significantly different among the groups, but MD values in the old group were significantly higher than those in the other groups.TV values of the old group were significantly lower than those of the other groups.Therefore, the increase in MD of the MLT began around the age of 60 years, and the decline in TV of the MLT began around the age of 20 years.This indicates that demyelination of the MLT began around the age of 20 years and accelerates around the age of 60 years.Based on the findings of this study, it was assumed that MCT degeneration began in the 20s and accelerated in the 60s, while MLT degeneration began in the 20s and accelerated in the 60s.
[38][39][40][41][42] Age-related changes affect dopaminergic manipulation; [20,43] hence, aging dopaminergic circuits have a strong correlation with memory decline.In contrast, VTA neurons responsive to reward-associated stimuli that were activated during social interaction and dopaminergic neurons, such as the MCT and MLT related to the PFC, have been shown to have an important relationship with social play behavior. [44,45]In addition, normal older adults exhibit a reduction in their social activity and interest, [46] which may be caused by a decline in social stimuli rewards relevant to aging of the MCT and MLT.Therefore, this finding might be an extension of the results these prior studies by showing that the connectivity of the structural pathway of the MCT and MLT is not only debilitated in older adults, but is also related to aging differences in the role of dopaminergic tracts, as previously reported.
In this study, we investigated age-related changes in the MCT and MLT using DTT and found that degenerative changes in the MCT and MLT were accelerated in the 60s.However, this study had some limitations.First, the number of groups was not matched.Second, the small number of subjects recruited in each group limits the generalizability of the results.Third, it is difficult to determine a clinical correlation because there is no clinically relevant evidence.Therefore, further studies that match a large number of subjects in each group and correlate clinical data are needed to compensate for these limitations.

Figure 1 .
Figure 1.(A) Seed regions of interest (ROIs) for mesocortical tract were placed on the ventral tegmental area (yellow); target ROIs for mesocortical tract were placed on the prefrontal cortexs (yellow); (B) seed regions of interest (ROIs) for mesolimbic tract were placed on the ventral tegmental area (red); target ROIs for mesolimbic tract were placed on the nucleus accumbens (red); (C) the reconstructed mesocortical tract; (D) the reconstructed mesolimbic tract.

Figure 2 .
Figure 2. (Left) Results of Bonferroni post hoc test in terms of the mesocortical tract among age groups; (right) correlations between age and the 3 DTT parameters of mesocortical tract.DTT = diffusion tensor tractography.

Figure 3 .
Figure 3. (Left) Results of Bonferroni post hoc test in terms of the mesolimbic tract among age groups; (right) correlations between age and the 3 DTT parameters of mesolimbic tract.DTT = diffusion tensor tractography.
Sixty-four right-handed, healthy participants (males: 40, females: 24, mean age: 47.45 ± 17.69 years; range: 20-79 years) who had no previous history of neurological, psychiatric, or physical illness and no brain lesions on conventional MRI (T1-weighted, T2-weighted, fluid-attenuated inversion recovery, or T2-weighted gradient recall echo images), as confirmed by a neuroradiologist, were enrolled in the present study.Participants were divided into 3 groups based on participants' age (young, middle-aged, and old).The young group included participants in their 20s and 30s, the middle-aged group included those in their 40s and 50s, and the old group Seo and Ryu • Medicine (2023) 102:46 Medicine the 3 DTI parameters (FA, MD, and TV) and age.Statistical significance was set at P < .05.The Kolmogorov-Smirnov test was used to test for normality among the outcome measures.

Table 1
Comparison of diffusion tensor image parameters of the mesocortical tract among the 3-age group.